Dscam1 in Pancrustacean Immunity: Current Status and a Look to the Future

Abstract

The Down syndrome cell adhesion molecule 1 (Dscam1) gene is an extraordinary example of diversity: by combining alternatively spliced exons, thousands of isoforms can be produced from just one gene. So far, such diversity in this gene has only been found in insects and crustaceans, and its essential part in neural wiring has been well-characterized for Drosophila melanogaster. Ten years ago evidence from D. melanogaster showed that the Dscam1 gene is involved in insect immune defense and work on Anopheles gambiae indicated that it is a hypervariable immune receptor. These exciting findings showed that via processes of somatic diversification insects have the possibility to produce unexpected immune molecule diversity, and it was hypothesized that Dscam1 could provide the mechanistic underpinnings of specific immune responses. Since these first publications the quest to understand the function of this gene has uncovered fascinating insights from insects and crustaceans. However, we are still far from a complete understanding of how Dscam1 functions in relation to parasites and pathogens and its full relevance for the immune system. In this Hypothesis and Theory article, we first briefly introduce Dscam1 and what we know so far about how it might function in immunity. By focusing on seven questions, we then share our sometimes contrasting thoughts on what the evidence tells us so far, what essential experiments remain to be done, and the future prospects, with the aim to provide a multiangled view on what this fascinating gene has to do with immune defense.

Keywords: alternative splicing; crustaceans; immunoglobulin domain; innate immunity; insects; isoform diversity.

Figure 1

Dscam1 in Drosophila melanogaster and known occurrence of Dscam1 in arthropods. (A) D. melanogaster Dscam1 genomic DNA structure contains 20 constant exons (black lines). Four exon clusters contain variable numbers of alternative exons (colored lines): exon 4 contains 12, exon 6 contains 48, exon 9 contains 33, and exon 17 contains 2 variants. (B) Dscam1 mRNA contains every constant exon (white boxes), but through the process of mutually exclusive alternative splicing, only one of each of the alternative exons is present in each mRNA; one exon combination for D. melanogaster is illustrated. (C) Dscam1 protein structure, where Ig indicates an immunoglobulin domain and FNIII indicates a fibronectin type III domain. The alternatively spliced exons encode the N-terminal halves of Ig2 and Ig3, all of Ig7, and the transmembrane domain. (D) Ig1 to Ig4 form a horseshoe configuration (24). Epitope I is one side of the horseshoe and in the nervous system engages in homophilic binding with identical Dscam1 isoforms coded for by the identical exon 4, 6, and 9 variants; the other side of the horseshoe, epitope II, has been proposed to bind to non-Dscam1 ligands, i.e., pathogen-related ligands. [(A–D) after (16)]. (E) Dscam1 as illustrated in (A–C) has, to date, only been found in pancrustaceans. Myriapods and chelicerates have diversified the Dscam gene family via other routes. *Crustacea is considered a paraphyletic group containing the hexapods; phylogeny follows Legg et al. (17).